Nuclear Pore Complexes Offer Clues to Gene Expression and Cancer

Polytene chromosomes revealed that nucleoporins pull double
duty as transcription factors regulating the activity of genes
active during early development.

Not only do nuclear pore complexes
serve as communication channels between
molecules and a cell's nucleus, but researchers
at the Salk Institute have now shown that
some of the pores' constituent proteins, called
nucleoporins, also pull double duty to regulate
gene activity.

This marks the first time nucleoporins' gene
regulatory function has been demonstrated in
multicellular organisms. These findings not
only reveal a new class of transcription factors
but they may offer new insights into the mechanisms
behind cancer.

It was previously unknown whether similar
regulatory properties were present in multicellular
organisms. For more than a decade,
however, scientists had known that when the
protein called Nup98, a nucleoporin, abnormally
fuses with certain proteins that regulate gene
expression, causing leukemia. What is more,
nucleoporins Nup214 and Nup88 are highly
over-expressed in other cancers, including colon
cancer and very aggressive forms of lung cancer.

Scientists had long questioned why these
components of the cell's transport channel are
implicated in cancer and had theorized that
the connection might stem from a problem
related to the conveyance of molecules in and
out of the nucleus.

To probe the role of these proteins, Martin
Hetzer, Hearst Endowment associate professor
in Salk's Molecular and Cell Biology Laboratory,
and his group studied the development of
salivary glands in fruit flies. Using antibodies,
the scientists were able to detect the binding of
Nup98, SEC13, and FG-containing nucleoporins
to specific genes on the polytene chromosomes.
When they did a three-dimensional reconstruction
of the nuclei, they found the nucleoporins
inside the nucleus.

"Very few studies have looked at nuclear
pore components for their potential role in
gene regulation in animal cells," says Hetzer.
"The fact that NPC components can interact
with genes inside the nucleus makes a lot more
sense in how they can regulate gene activity.
The gene doesn't go to the pore; the pore
protein goes to the gene."

The nucleoporins don't regulate all genes,
but are required for a subset of genes,
including developmentally regulated genes,
which are turned on and off in a controlled
manner during cell differentiation and tissue
development.

"What is exciting to us is that they are
key regulators for developmental genes and
also potential markers for causes of cancer,"
Hetzer explains.